CN103910780A - Preparation method of L-alanine-L-glutamine compound - Google Patents
Preparation method of L-alanine-L-glutamine compound Download PDFInfo
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- CN103910780A CN103910780A CN201410140127.3A CN201410140127A CN103910780A CN 103910780 A CN103910780 A CN 103910780A CN 201410140127 A CN201410140127 A CN 201410140127A CN 103910780 A CN103910780 A CN 103910780A
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Abstract
The invention discloses a preparation method of an L-alanine-L-glutamine compound. The preparation method comprises the following steps: adding a compound 10 into ammonia water for performing ammonolysis reaction to obtain the L-alanine-L-glutamine compound, wherein the compound 10 is obtained by the following steps: reacting sulfoxide chloride with a compound 8 to obtain a compound 9 and adding the compound 9 into glutamine under the alkaline condition to obtain the compound 10. According to the preparation method, the used raw materials are easily available, the reaction conditions are mild, the steps are simple, the reaction does not need to be carried out at the ultralow temperature, a flammable and combustible reagent is not used, the large-scale industrial production is facilitated, the safety is high, the reaction yield is relatively high, the cost is relatively low, and the application prospect is wide.
Description
Technical field
The present invention relates to a kind of preparation method of ALANINE-L-glutamine.
Background technology
Chemistry ALANINE-L-glutamine by name of novel parenteral nutrition medicine power peptide, structural formula is suc as formula shown in I, be applied to those patients that need to supplement glutamine and comprise those patients in katabolism and hypermetabolism situation, obtained the preferential examination and approval authority of U.S. FDA at present.III phase clinical effectiveness shows formula I compound and current parenteral nutrition medicine salable, its effect more by force, more effective.
Chinese patent CN103387600A discloses a kind of preparation method of power peptide, and its synthetic route is as follows:
In the method, synthesis step complexity, and side reaction is many, so the finished product yield is low, environmental pollution is serious, can not scale operation.
Consider the market outlook that power peptide is good, therefore need the novel method of exploitation preparation.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method of preparing ALANINE-L-glutamine, the above-mentioned defect existing to overcome prior art.
For solving the problems of the technologies described above, the present invention adopts following technical scheme to realize:
A preparation method for ALANINE-L-glutamine compound, comprises the steps: compound 10 to add in ammoniacal liquor and carry out ammonolysis reaction, obtains described ALANINE-L-glutamine compound; Described compound 10 structural formulas are as follows:
The structural formula of described ALANINE-L-glutamine compound is as follows:
Wherein, described compound 10 obtains as follows: sulfur oxychloride and compound 8 reactions are obtained to compound 9, then under alkaline condition, in glutamine, add compound 9, can obtain compound 10; The structural formula of described compound 8 and compound 9 is as follows respectively:
Wherein, described R is that carbonatoms is 1～20 alkyl, the alkyl that is preferably 1～3 for carbon atom, and better is methyl.
Described ammonia add-on is 0.8～1 times of described compound 10 weight.
Described ammonolysis reaction comprises the steps:
Compound 10 is added in ammoniacal liquor, under 60～65 ℃, 1.0～1.5Mpa condition, react 5-6 hour, react complete pressure release, in 60～65 ℃ concentrated, until separate out white solid, cooling adds methyl alcohol crystallization slightly, methyl alcohol adds rear cooling water temperature, lowers the temperature and processes below to obtain product in 10 ℃.
The present invention further discloses the preparation method of described compound 9, comprise the steps:, under-8～-2 degrees Celsius, in sulfur oxychloride, to drip compound 8, within 1-2 hour, drip off, temperature control reaction 5～6 hours, is warming up to room temperature naturally, slowly be heated to 50～55 degrees Celsius, react 5～6 hours; Suitably, after cooling, underpressure distillation, collects cut and obtains described compound 9.
The mol ratio of sulfur oxychloride and compound 8 is 3:1.
As preferred version, in sulfur oxychloride and compound 8 reaction systems, also add appropriate pyridine, adding pyridine is as solvent, those skilled in the art can be easy to select suitable add-on.
Those skilled in the art can, according to the characteristic of this type of reaction, select best temperature of reaction, are generally 50-55 degree Celsius, and the described reaction times, with till reacting completely, is generally 5-6 hour.
The present invention also further discloses the preparation method of compound 10, comprises the steps:
Glutamine and suitable quantity of water, toluene are mixed, while being cooled to 0-5 ℃, start to add sodium hydroxide solution, then drip the mixing solutions of chlorpromazine chloride and toluene, drip sodium hydroxide maintenance pH is 10～11 simultaneously, and temperature is reacted 1 hour between 0-5 ℃, at 10-15 ℃, react 2 hours again, then divide toluene layer, in water, adding Industrial Salt and regulating PH with hydrochloric acid is 1-2, and adularescent solid is separated out, be cooled to 5 ℃ of following filtrations, oven dry obtains product and obtains described compound 10.
The mol ratio of glutamine and compound 9 is 1:1.
Wherein water and toluene are as solvent, and Industrial Salt is to reduce the solubleness of product in water, thereby improves output, and those skilled in the art can be easy to select suitable add-on.
Positive progressive effect of the present invention is:
1, the raw material using in preparation method of the present invention is easy to get, reaction conditions gentleness, and step is simple, does not need to react under condition of ultralow temperature, does not use inflammable and explosive reagent, is suitable for large-scale industrial production, safe; And reaction yield is higher, cost is lower.
2, ALANINE-L-glutamine disclosed by the invention, its preparation method is simple, and by a synthetic front three-step reaction step, reaction time is shorter, and reaction conditions gentleness has reduced production cost and the pollution to environment greatly, is with a wide range of applications.
Embodiment
Provide preferred embodiment of the present invention below, to describe technical scheme of the present invention in detail.
In following each embodiment, unless otherwise indicated beyond, all per-cent is all mol ratio.
Embodiment 1
The preparation of compound 9, wherein R is methyl:
35.7 grams of sulfur oxychlorides, add 0.5 milliliter of pyridine, and ice is cooled to subzero 5 degree, drips (90%) 11 gram of Pfansteihl, under control zero temperature, below 5 degree, within 1 and a half hours to 2 hours, drip off temperature control reaction 5～6 hours, naturally be warming up to room temperature, be slowly heated to 50～55 degree, react 5～6 hours.Suitably, after cooling, underpressure distillation, collects 10 mmhg 44～48 degree cuts and obtains 14 grams of products, and yield is 90.3%.
Embodiment 2
The preparation of compound 9, wherein R is methyl:
357 grams of sulfur oxychlorides, add 5 milliliters of pyridines, and ice is cooled to subzero 5 degree, drips (90%) 110 gram of Pfansteihl, under control zero temperature, below 5 degree, within 1 and a half hours to 2 hours, drip off temperature control reaction 5～6 hours, naturally be warming up to room temperature, be slowly heated to 50～55 degree, react 5～6 hours.Suitably, after cooling, underpressure distillation, collects 10 mmhg 44～48 degree cuts and obtains 139.3 grams of products, and yield is 89.9%.
Embodiment 3
The preparation of compound 10, wherein R is methyl:
In reactor, add 1000g water, 850g toluene and 250gL-glutamine, be cooled to 0-5 ℃, under stirring, add 203g sodium hydroxide solution to L-glutaminate all to dissolve, slowly drip again the mixing solutions of 128.9g chlorpromazine chloride and 170g toluene, drip PH that sodium hydroxide solution maintains reaction solution between 10～11 simultaneously, after dropwising, maintain the temperature at 0-5 ℃, PH reacts 1 hour between 10～11, at 10-15 ℃, react 2 hours again, then divide toluene layer, in water, adding 250g Industrial Salt and regulating PH with hydrochloric acid is 1-2, adularescent solid is separated out, be cooled to 5 ℃ of following filtrations, oven dry obtains product 210.4g, yield is 87.6%.
Embodiment 4
The preparation of compound 10, wherein R is methyl:
In reactor, add 10kg water, 8.5kg toluene and 2.5kg L-glutaminate, be cooled to 0-5 ℃, under stirring, add 2kg sodium hydroxide solution to L-glutaminate all to dissolve, slowly drip again the mixing solutions of 1289g chlorpromazine chloride and 1.7kg toluene, drip PH that sodium hydroxide solution maintains reaction solution between 10～11 simultaneously, after dropwising, maintain the temperature at 0-5 ℃, PH reacts 1 hour between 10～11, at 10-15 ℃, react 2 hours again, then divide toluene layer, in water, adding 2.5kg Industrial Salt and regulating PH with hydrochloric acid is 1-2, adularescent solid is separated out, be cooled to 5 ℃ of following filtrations, oven dry obtains product 2100g, yield is 87.4%.
Embodiment 5
The preparation of compound L-L-Ala-L-glutamine, wherein R is methyl:
In reactor, squeeze into 1000g water, vacuum condition stirs lower logical ammonia and prepares ammoniacal liquor.After logical 400g ammonia, stop stirring, open reaction kettle cover and drop into 450g intermediate 10.The complete closed reactor that feeds intake, opens and stirs and hot water circulation temperature reaction.In the time that reacting liquid temperature rises to 60～65 ℃, pressurize 1.0～1.5MPa reaction 6 hours, reacts complete pressure release, in 60～65 ℃ concentrated, until separate out white solid, cooling adds methyl alcohol crystallization slightly.Methyl alcohol adds rear cooling water temperature, lowers the temperature in 10 ℃ of following processing, obtains product 330.3g, and yield is 80%.
Embodiment 6
The preparation of compound L-L-Ala-L-glutamine, wherein R is methyl:
In reactor, squeeze into 10kg water, vacuum condition stirs lower logical ammonia and prepares ammoniacal liquor.After logical 4kg ammonia, stop stirring, open reaction kettle cover and drop into 4.5kg intermediate 10.The complete closed reactor that feeds intake, opens and stirs and hot water circulation temperature reaction.In the time that reacting liquid temperature rises to 60～65 ℃, pressurize 1.0～1.5MPa reaction 6 hours, reacts complete pressure release, in 60～65 ℃ concentrated, until separate out white solid, cooling adds methyl alcohol crystallization slightly.Methyl alcohol adds rear cooling water temperature, lowers the temperature in 10 ℃ of following processing, obtains product 3.28kg, and yield is 79.4%.
Claims (8)
1. a preparation method for ALANINE-L-glutamine compound, is characterized in that, comprises the steps: compound 10 to add in ammoniacal liquor and carry out ammonolysis reaction, obtains described ALANINE-L-glutamine compound; Described compound 10 structural formulas are as follows:
The structural formula of described ALANINE-L-glutamine compound is as follows:
Wherein, described compound 10 obtains as follows: sulfur oxychloride and compound 8 reactions are obtained to compound 9, then under alkaline condition, in glutamine, add compound 9, can obtain compound 10; The structural formula of described compound 8 and compound 9 is as follows respectively:
Wherein, described R is that carbonatoms is 1～20 alkyl.
2. method according to claim 1, is characterized in that, R is that carbon atom is 1～3 alkyl.
3. method according to claim 1, is characterized in that, R is methyl.
4. according to the method described in claim 1-3 any one, it is characterized in that, the preparation method of described compound 9, comprise the steps:, under-8～-2 degrees Celsius, in sulfur oxychloride, to drip compound 8, within 1-2 hour, drip off, temperature control reaction 5～6 hours, naturally be warming up to room temperature, be slowly heated to 50～55 degrees Celsius, react 5～6 hours; Suitably, after cooling, underpressure distillation, collects cut and obtains described compound 9, and the mol ratio of described sulfur oxychloride and compound 8 is 3:1.
5. method according to claim 4, is characterized in that, in sulfur oxychloride and compound 8 reaction systems, also adds appropriate pyridine.
6. method according to claim 4, it is characterized in that, the preparation method of described compound 10, comprise the steps: glutamine and suitable quantity of water, toluene mixes, while being cooled to 0-5 ℃, start to add sodium hydroxide solution, then drip the mixing solutions of chlorpromazine chloride and toluene, drip sodium hydroxide maintenance pH is 10～11 simultaneously, temperature is reacted 1 hour between 0-5 ℃, at 10-15 ℃, react 2 hours again, then divide toluene layer, in water, adding Industrial Salt and regulating PH with hydrochloric acid is 1-2, adularescent solid is separated out, be cooled to 5 ℃ of following filtrations, oven dry obtains product and obtains described compound 10, the mol ratio of described glutamine and compound 9 is 1:1.
7. method according to claim 6, it is characterized in that, described ammonolysis reaction comprises the steps: compound 10 to add in ammoniacal liquor, under 60～65 ℃, 1.0～1.5Mpa condition, react 5-6 hour, react complete pressure release, concentrated in 60～65 ℃, until separate out white solid, cooling adds methyl alcohol crystallization slightly, and methyl alcohol adds rear cooling water temperature, lowers the temperature and processes below to obtain product in 10 ℃.
8. according to the method described in claim 1 or 7, it is characterized in that, described ammonia add-on is 0.8～1 times of described compound 10 weight.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106608903A (en) * | 2017-02-09 | 2017-05-03 | 中卫市创科知识产权投资有限公司 | Production technology of N-(2)-L-alanyl-L-glutamine |
| CN113603582A (en) * | 2021-07-28 | 2021-11-05 | 苏州永诺泓泽生物科技有限公司 | Method for preparing D- (+) -2-chloropropionyl chloride by adopting micro-channel continuous flow reactor |
| CN113773190A (en) * | 2021-07-28 | 2021-12-10 | 苏州永诺泓泽生物科技有限公司 | Preparation method of D- (+) -2-chloropropionyl chloride |
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| US5380934A (en) * | 1992-10-29 | 1995-01-10 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing alanylgutamine |
| CN101463075A (en) * | 2007-12-19 | 2009-06-24 | 天津天成制药有限公司 | Preparation of N(2)-L-alanyl-L-glutamine |
| CN101633614A (en) * | 2009-08-18 | 2010-01-27 | 山东鲁抗立科药物化学有限公司 | Synthesis method of D-(+)-2-chloropropionyl chloride |
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2014
- 2014-04-09 CN CN201410140127.3A patent/CN103910780A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380934A (en) * | 1992-10-29 | 1995-01-10 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing alanylgutamine |
| CN101463075A (en) * | 2007-12-19 | 2009-06-24 | 天津天成制药有限公司 | Preparation of N(2)-L-alanyl-L-glutamine |
| CN101633614A (en) * | 2009-08-18 | 2010-01-27 | 山东鲁抗立科药物化学有限公司 | Synthesis method of D-(+)-2-chloropropionyl chloride |
Non-Patent Citations (1)
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| 陈再新等: "Ｎ(２)-Ｌ-丙氨酰-Ｌ-谷氨酰胺的合成工艺研究", 《精细与专用化学品》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106608903A (en) * | 2017-02-09 | 2017-05-03 | 中卫市创科知识产权投资有限公司 | Production technology of N-(2)-L-alanyl-L-glutamine |
| CN113603582A (en) * | 2021-07-28 | 2021-11-05 | 苏州永诺泓泽生物科技有限公司 | Method for preparing D- (+) -2-chloropropionyl chloride by adopting micro-channel continuous flow reactor |
| CN113773190A (en) * | 2021-07-28 | 2021-12-10 | 苏州永诺泓泽生物科技有限公司 | Preparation method of D- (+) -2-chloropropionyl chloride |
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Application publication date: 20140709 |